Daniel H. Polk

Glucocorticoid regulation of surfactant components in immature lambs.

To assess effects of dose and duration of glucocorticoid exposure on maturation of the fetal lung, we administered single or multiple doses of betamethasone (0.5 mg/kg im) to pregnant sheep for 2 or 21 days before preterm delivery at 125 days of gestation. Lung function (compliance, lung volume at 40 cmH2O pressure, and ventilatory efficiency index) was increased after two to four weekly doses of glucocorticoid (2.5- to 4-fold increase) and after 48 h of exposure (1.4- to 2.3-fold). Total protein of lavage fluid decreased similarly with three doses, four doses, and 48 h of treatment. In lambs with long-term exposure to betamethasone, there was a similar, dose-dependent increase in concentrations of saturated phosphatidylcholine and surfactant proteins A (SP-A) and B (SP-B) (maximal 2- to 3-fold in tissue and 10- to 15-fold in lavage fluid). Levels of SP-A and SP-B were closely correlated in lavage fluid. In animals treated for 48 h, only tissue SP-B was increased (2.7-fold). We conclude that 48 h of glucocorticoid treatment improves lung function in the premature lamb without a detectable increase in lavage surfactant components and that longer exposure to antenatal glucocorticoid increases surfactant lipid and proteins in a coordinated fashion. The enhanced response with repetitive dosing indicates that the process of glucocorticoid-induced lung maturation is either reversible and/or gestational age dependent.

Minimum interval from fetal betamethasone treatment to postnatal lung responses in preterm lambs

OBJECTIVE We hypothesized that fetal betamethasone exposure for < 24 hours would improve postnatal lung function in preterm lambs. STUDY DESIGN Singleton fetal sheep were randomized to receive by ultrasonographically guided fetal injections of 0.5 mg/kg betamethasone or saline solution either 8 or 15 hours before preterm delivery and postnatal assessment of lung function. RESULTS After the 15-hour fetal treatment-to-delivery interval, betamethasone-treated lambs had twofold improvement in compliance and lung volumes, a fourfold to fivefold decrease in edema index, and higher blood pressures than saline solution-treated lambs. Postnatal lung function or lung volumes did not improve for the 8-hour treatment-to-delivery interval, although betamethasone decreased the pulmonary edema and increased the postnatal blood pressure. CONCLUSIONS The minimal interval from fetal exposure to corticosteroids to delivery for improved postnatal lung function was between 8 and 15 hours. Corticosteroid effects on pulmonary edema and blood pressure occurred within 8 hours.

Dopamine pharmacokinetics in critically ill newborn infants.

To compare clinical responses with plasma concentrations of dopamine and to compare dopamine pharmacokinetics in infants of different gestational age or clinical condition, dopamine was administered under carefully controlled conditions of dose and rate of infusion. The dose was increased stepwise from 1 to 2, to 2 to 4, and 4 to 8 micrograms/kg/min. Plasma concentrations of catecholamines, including dopamine, were compared with blood pressure, heart rate, and Doppler cardiac output. The data were analyzed to determine the threshold or minimal plasma concentration of dopamine necessary to produce discernible effects. Plasma clearance rate was calculated from steady-state plasma concentrations. The average threshold for increases in mean arterial pressure was 50% below that for increases in heart rate. Improvements in arterial pressure were noted before and at lower thresholds than for increases in heart rate. Serial echocardiographic data showed dose-dependent increases in cardiac output and stroke volume without significant change in heart rate or systemic vascular resistance. Thresholds and plasma clearance values were similar in infants of gestational age 27 to 42 weeks and birth weights 900 to 4300 g. Administration of dopamine at initial dosages lower than commonly recommended, followed by incremental increase in dose, may be associated with improved left ventricular performance with avoidance of undesirable tachycardia and arrhythmias.

Plasma Thyroid Hormones and Prolactin in Premature Infants and Their Mothers after Prenatal Treatment with Thyrotropin-Releasing Hormone

ABSTRACT: We assayed TSH, triiodothyronine, free thyroxine, and prolactin (PRL) in plasma of women and infants participating in a trial of prenatal thyrotropin-releasing hormone (TRH) treatment for prevention of newborn lung disease. Women in labor at 26–34 wk of gestation received 400 μg of TRH i.v. every 8 h (one to four doses) plus 12 mg betamethasone (one or two doses); controls received saline plus betamethasone. Mean cord concentrations in control infants were TSH 9.7 mU/L, triiodothyronine 0.6 nmol/L (40.2 ng/dL), free thyroxine 14.4 pmol/L (1.13 ng/dL), and PRL 67.6 μg/L. TRH increased maternal plasma TSH by 100% at 2–4 h after treatment and decreased levels by 28–34% at 5–36 h. In cord blood of treated infants delivered at 2–6 h, TSH, triiodothyronine, and PRL were all increased about 2-fold versus control, and free thyroxine was increased 19%; the response was similar after one, two, three, or four doses of TRH. In treated infants delivered at 13–36 h, cord TSH and triiodothyronine levels were decreased 62 and 54%, respectively, and all thyroid hormones were lower after birth at 2 h of age versus control. We conclude that prenatal TRH administration increases thyroid hormones and PRL in preterm fetuses to levels similar to those normally occurring at term. Pituitary-thyroid function is transiently suppressed after treatment to a greater extent in fetus than mother, and infants born during the early phase of suppression do not have the normal postnatal surge in thyroid hormones.

Postnatal Cardiovascular and Metabolic Responses to a Single Intramuscular Dose of Betamethasone in Fetal Sheep Born Prematurely by Cesarean Section

ABSTRACT: Although the benefits of antenatal hormone treatment are well accepted, most studies have reported only pulmonary effects. There is evidence of beneficial cardiovascular and metabolic effects in studies using chronically catheterized animals; however because of the route of administration, the results are not directly applicable to clinical strategies. We previously demonstrated significant pulmonary effects in animals treated antenatally with a single, direct fetal, intramuscular injection of glucocorticoids. This study was performed to determine the effects of a single fetal injection of betamethasone (BETA) alone or in combination with thyroxine (T4) on cardiovascular and metabolic responses after preterm birth. Hemodynamic and metabolic responses at birth were determined in fetuses (126-d gestation; term = 150 d) treated with ultrasound-guided intramuscular injections of 0.5 mg/kg BETA (n = 7), BETA plus 60 g/kg T4 (n = 7), or saline (SAL, n = 9). After 48 h, lambs were delivered by cesarean section and studied for 3 h. BETA treatment increased mean arterial blood pressure [56 ± 6 (SEM) versus 42 ± 3 mm Hg], heart rate (152 ± 5 versus 123 ± 4 beats/min), and cardiac output (467 ± 17 versus 349 ± 36 mL/min/kg) versus SAL. Responses of BETA + T4-treated animals were not different from animals treated with BETA alone. Glucose and FFA were similar among all groups. The increase in catecholamine levels normally seen at birth was significantly attenuated in both the BETA and BETA + T4-treated animals. A single, intramuscular injection of glucocorticoids 48 h before delivery improves cardiovascular responses to preterm birth. This effect is not augmented by concomitant administration of T4.

Pharmacokinetics of dopamine in critically ill newborn infants

Dopamine pharmacokinetics was investigated in 14 critically ill newborn infants ranging from 27 to 43 weeks of gestational age and from 0.9 to greater than 4 kg birth weight. Plasma clearance rate was determined from dopamine levels during controlled infusions under actual clinical conditions. Dopamine was administered in stepwise increasing doses up to 8 micrograms/kg/min. Dopamine concentration and dopamine clearance rate were determined from duplicate samples drawn during each infusion in each patient. Steady-state plasma dopamine concentrations and plasma clearance rates were observed within 20 minutes at each infusion. Plasma dopamine concentration ranged from 0.5 ng/ml before infusion to almost 70 ng/ml at an infusion rate of 4 to 8 micrograms/kg/min. There was a linear correlation between infusion rate and plasma dopamine concentration (r = 0.68, p less than 0.001). Neither plasma dopamine concentration nor infusion rate had a significant effect on clearance rate. These data are consistent with first-order kinetics for administered dopamine in critically ill neonates over the range of concentrations studied.

Epidermal growth factor acts as a corticotropin-releasing factor in chronically catheterized fetal lambs.

Epidermal growth factor (EGF) has been reported to stimulate adrenocorticotropin hormone (ACTH), growth hormone and prolactin secretion from pituitary tissue in vitro, and in large doses evokes ACTH secretion in adult sheep in vivo. In order to assess a possible role for EGF in the pituitary hyperfunction characteristic of the in utero fetus, we measured changes in plasma immunoreactive ACTH concentrations after acute administration of saline, purified mouse EGF or synthetic ovine corticotropin releasing factor (CRF) to chronically catheterized fetal sheep. Both CRF and EGF were associated with increases in plasma immunoreactive ACTH concentrations. Peak values 60 min after 10-micrograms injections of either EGF or CRF increased from baseline ACTH values of 61 +/- 11 pg/ml to 191 +/- 37 and 178 +/- 25 pg/ml, respectively. Dose-response studies indicate that at low doses (less than 20 micrograms) EGF is as potent a stimulus for ACTH release as CRF. EGF infusion was not associated with detectable changes in circulating CRF, catecholamines, arginine vasopressin levels, or plasma growth hormone concentrations. We speculate that EGF may be important in the regulation of pituitary function in the developing mammalian fetus.

Antenatal Glucocorticoids Alter Postnatal Preterm Lamb Renal and Cardiovascular Responses to Intravascular Volume Expansion

We assessed renal and cardiovascular function in preterm newborn lambs after antenatal glucocorticoid exposure. Pregnant ewes were randomly assigned to receive betamethasone or saline via either direct fetal or maternal injection at 122 d gestation. Lambs were delivered 15 h later, and cardiovascular and renal function was assessed. Two hours after delivery, baseline urine flow, urinary sodium excretion, and urinary osmolar clearance were similar in all groups. Volume expansion (saline, 2.5% of body weight, for 10 min) increased values for urine flow (0.23 ± 0.04 to 0.58 ± 0.09 mL·min−1·kg−1), urinary sodium excretion (29.7 ± 5.8 to 76.2 ± 12.3 μEq·min−1·kg−1), and osmolar clearance (12.2 ± 1.2 to 24.3 ± 1.6 mL/100 mL GFR) in the fetal group. Increases in urine values were also observed in the maternal group, but control values did not change significantly. Mean arterial pressure was increased in both betamethasone-treated groups relative to controls. Short-term antenatal betamethasone exposure 1) augments preterm newborn kidney adaptive responses to acute volume expansion, and 2) increases postnatal blood pressure in preterm newborn lambs.

Single Dose Fetal Betamethasone Administration Stabilizes Postnatal Glomerular Filtration Rate and Alters Endocrine Function in Premature Lambs

These studies determined the effects of fetal treatment with betamethasone alone, or in combination with thyroid hormone (thyroxine; T4), on postnatal renal and endocrine adaptations in preterm newborn lambs. Ovine fetuses (126 d of gestation; term = 150 d) received single, ultrasound-guided intramuscular injections of saline, 0.5 mg/kg betamethasone (Celestone Soluspan®, or 0.5 mg/kg betamethasone plus 60 μg/kg T4. After 48 h, lambs were delivered, treated with surfactant (Survanta®, 100 mg/kg), and ventilated for 3 h. Due to maintained urine flow in the betamethasone-treated animals and a significant decrease in the saline group, betamethasone versus saline urine flow values (0.11 ± 0.03versus 0.03 ± 0.004 mL·min-1·kg-1) were significantly elevated by the end of studies. GFR (1.5 ± 0.3 versus 0.8 ± 0.2 mL·min-1·kg-1) and mean blood pressure (61± 4 versus 42 ± 3 mm Hg) values also were higher in the betamethasone-treated animals. Although renal blood flow, renal plasma flow, and fractional sodium excretion rates did not differ, betamethasoneversus saline values for the filtration fraction (11.9 ± 1.5versus 7.4 ± 1.5%) and total sodium reabsorption (196± 38 versus 81 ± 16μEq·min-1·kg-1) were increased. Betamethasoneversus saline treatment also was associated with significant reductions in plasma angiotensin II (125 ± 23 versus 550± 140 pg/mL) and AVP (116 ± 19 versus 230 ± 77 pg/mL) levels. Overall, the effects of combined betamethasone + T4 treatment were similar to the effects of betamethasone alone. Conclusions: 1) fetal betamethasone injection 48 h before delivery stabilizes GFR and significantly alters endocrine function in preterm newborn lambs, and 2) the addition of T4 does not augment betamethasone-induced renal and endocrine responses.

Corticosteroids, thyrotropin-releasing hormone, and antioxidant enzymes in preterm lamb lungs

ABSTRACT: Forty-three twin lamb fetuses of 121 ± 1 d gestation were catheterized and received i.v. saline (n = 8), 0.75 mgjkg/h cortisol for 60 h (n = 15), 5 μg/kg thyrotropin-releasing hormone (TRH) every 12 h for five doses (n = 9), or cortisol and TRH (n = 11) before delivery at 128 ± 1 d. After delivery, the lambs were randomized for natural sheep surfactant treatment or sham treatment, ventilated for 75 min, and killed. Superoxide dismutase, catalase, and glutathione peroxidase activities were measured in fetal lung tissue. Superoxide dismutase and catalase activities were increased in both the corticosteroid (p < 0.001) and the corticosteroid with TRH (p < 0.01) groups. Glutathione peroxidase activity was higher after prenatal corticosteroid treatment, but statistical significance was not reached (p = 0.06). Although prenatal exposure to corticosteroids increased superoxide dismutase, catalase, and glutathione peroxidase activities, TRH alone or TRH added to corticosteroids provided no additional benefit. Lambs treated with surfactant had higher lung catalase activities than lambs that did not receive surfactant, probably secondary to the presence of catalase activity in the surfactant preparation. Increased pulmonary antioxidant enzyme activity may be an additional feature of the overall beneficial effect of corticosteroids on fetal lung development. (Pediatr Res 30: 518–521, 1991)